H00102--00A, Front mat Genesis

by Charles Baum

  ously at hydrothermal vents, where the less acidic vent water contacts

  the more acidic ocean water. These bubbles form primitive cell-like

  structures that enclose metabolic chemicals. The bubbles also main-

  tain a strong contrast of acidity between inside and outside—an ener-

  getic difference that can promote metabolic reactions.

  By contrast, Wächtershäuser advocates “flat life.” The first self-

  replicating entity in his proposed Iron–Sulfur World was, as we saw in

  Chapter 8, a thin layer of chemical reactants on a sulfide mineral sur-

  face. The entity grew laterally, spreading from mineral grain to mineral

  grain as an invisibly thin organic film. Bits of these layers could break

  off and reattach to other rocks, like cloned colonies. Given time, differ-

  ent minerals and environmental conditions might have induced varia-

  tions in the film, fostering new “species” of flat life.

  The bold, heretical concept of flat life—a self-replicating chemical

  layer of molecules built on a solid mineral foundation—raises an in-

  triguing geochemical possibility. A simple layered collection of mol-

  ecules might be more tolerant of high temperatures and other

  environmental extremes than life based on nucleic acids, which break

  down close to 100°C. If so, then colonies of flat life might exist today in

  deep zones of Earth’s crust. Such film-like molecular systems might

  persist for eons, because they survive at extreme conditions beyond

  the predation of more efficient cellular life.

  If so, how would we know? Such a layer would be invisible under

  an ordinary light microscope and would appear as a nondescript film

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  using more powerful atomic microscopes. Flat life would also be unde-

  tectable in standard biological assays, which rely on the presence of

  DNA and proteins. Is it possible that layer life is abundant on Earth

  today, yet remains overlooked?

  There’s much to learn about the emergence of self-replicating

  chemical systems. Whether they first formed as chainlike peptides or

  films, self-replicating molecular systems appear to be a necessary ante-

  cedent to life. Nevertheless, a self-replicating metabolism by itself is

  not sufficient for life as we know it, and many scientists still argue that

  genetics came first.

  16

  The RNA World

  It is generally believed that there was a time in the early

  history of life on Earth when RNA served as both the genetic

  material and the agent of catalytic function.

  Gerald Joyce, 1991

  In spite of the elaborate detail of Wächtershäuser’s Iron–Sulfur

  World, most origin experts dismiss the idea of a purely metabolic

  life-form in favor of a genetics-first scenario. In order to repro-

  duce, even the simplest known cell must pass volumes of information

  from one generation to the next, and the only known way to store and

  copy that much information is with a genetic molecule similar to DNA

  or RNA.

  No one has thought more deeply about genetics and the origins of

  life than Leslie Orgel at the Salk Institute for Biological Studies in San

  Diego. His classic 1968 paper, “Evolution of the genetic apparatus,” has

  guided generations of researchers, and he continues to exert a tremen-

  dous influence on origin theory and experiment. Orgel states that the

  central dilemma in understanding a genetic origin of life is the identi-

  fication of a stable, self-replicating genetic molecule—a polymer that

  simultaneously carries the information to make copies of itself and

  also catalyzes that replication. Accordingly, he catalogs four broad ap-

  proaches to the problem of jump-starting such a genetic organism.

  One possibility is the emergence of a self-replicating peptide of the

  kind made by Reza Ghadiri’s group at Scripps, or perhaps a protenoid

  as championed by Sidney Fox. The idea that proteins emerged first and

  then “invented” DNA holds some appeal, because amino acids, the con-

  stituents of proteins, are thought to have been available in the prebi-

  otic environment. The problem is that the random prebiotic assembly

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  216

  GENESIS

  of amino acids would have been a messy business, as Fox’s critics were

  quick to point out. Cells have learned how to form neat, chainlike poly-

  mers—the proteins essential to life. But left to their own devices, amino

  acids link together in irregular, undisciplined clusters—hardly the stuff

  of genetics.

  The second of Orgel’s possibilities, the simultaneous evolution of

  proteins and DNA, seems even less likely, because it requires the emer-

  gence of not one but two improbable macromolecules.

  Graham Cairns-Smith’s Clay World scenario provides an intrigu-

  ing third option, with genetic-like sequences of elements replicating

  and acting as templates for organic assembly. So far, however, the Clay

  World scenario is totally unsupported by experimental evidence.

  The fourth and favored genetics-origin model of Orgel and many

  followers is based on a nucleic-acid molecule such as RNA—a single-

  stranded polymer that acts both as a carrier of information and as a

  catalyst that promotes self-replication. Orgel proposed this model in

  1968, long before any experimental evidence supported such a notion.

  “I must confess to a strong, longstanding bias in favor of [this] expla-

  nation,” he remarked recently. “It is, at the very least, the model that

  can be studied most easily in the laboratory.”

  How to choose? When evaluating various origin-of-life models,

  scientists aren’t restricted to chemical experiments alone. The metabo-

  lism-first models of Wächtershäuser, de Duve, and others are equally

  influenced by top-down studies of molecular phylogeny, which point

  to deeply embedded, primordial biochemical pathways. The principle

  of continuity demands an unbroken path from ancient geochemisty to

  modern biochemistry. Hence, the citric acid cycle that lies at the heart

  of all modern metabolism becomes a prime target for studies of

  protometabolism.

  In like fashion, top-down studies of molecular genetics have ze-

  roed in on RNA as the essential core molecule of ancient genetics.

  THE RNA WORLD

  Few events have electrified the origin-of-life community as much as

  the early 1980s discovery of RNA ribozymes—strands of RNA that not

  only carry genetic information, but also act as catalysts. Sidney Altman

  of Yale and Thomas Cech of the University of Colorado independently

  demonstrated that a particular segment of RNA can accelerate key bio-

  THE RNA WORLD

  217

  chemical reactions. This startling finding, which won Altman and Cech

  the Nobel Prize in 1989, inspired a new vision of life’s origin.

  Modern life relies on two complexly interrelated molecules: DNA,

  which carries information, and proteins, which perform chemical

  functions. This interdependence leads to a kind of chicken-and-egg

  dilemma: Proteins make and maintain DNA, but DNA carries the in-

  stru
ctions to make proteins. Which came first? RNA, it turns out, has

  the potential to do both jobs

  The RNA World theory quickly emerged following the discovery

  of ribozymes. It champions the central role of genetic material in the

  dual tasks of catalyst and information transfer. Over the years, “RNA

  World” has come to mean different things to different people, but three

  precepts are common to all versions of the theory: (1) Once upon a

  time, RNA rather than DNA stored genetic information; (2) ancient

  RNA replication followed the same rules as modern DNA replication

  by matching pairs of bases: A-U (the pyrimidine uracil, whose DNA

  equivalent is thymine) and C-G; and (3) ancient RNA played the same

  catalytic roles as modern protein enzymes. In this scenario, the first

  life-form was simply a self-replicating strand of RNA, perhaps enclosed

  in a protective lipid membrane. According to most versions of this hy-

  pothesis, modern metabolism emerged later, as a means to make RNA

  replication more efficient.

  Two factors may have contributed to the speed with which the

  RNA World idea caught on. For one thing, a generation after the

  Miller–Urey experiment, there were still few solid clues about how to

  make the transition from the prebiotic soup to cellular life. The origin-

  of-life community was poised to try something new, and RNA pro-

  vided a compelling original angle, rich in experimental possibilities. In

  addition, evidence of the dual role of RNA, as both catalyst and carrier,

  proved seductive to the new generation of biologists, who were born

  and raised in the age of molecular genetics. To many researchers, life

  and genetics are synonymous, so the RNA World idea resonates deeply.

  The more that biologists learn about RNA, the more remarkably

  versatile it seems. One big surprise came from the study of ribosomes,

  lumpy cellular structures that help to assemble proteins. Ribosomes

  consist of a complex intergrowth of proteins and several RNA strands.

  Many biologists assumed that the proteins play their usual active role

  as the enzymes that do the actual assembly work, while RNA merely

  holds the ribosomes together. However, recent studies prove just the

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  GENESIS

  opposite—that RNA mediates the critical step of linking up the

  protein’s constituent amino acids. In essence, RNA does the heavy lift-

  ing in protein assembly—a discovery that strongly reinforces RNA’s

  presumed ancient role in biochemistry.

  RNA’s probable antiquity is underscored by a growing list of other

  biochemical studies. For example, RNA nucleotides play key structural

  roles in a variety of essential biological catalysts called coenzymes.

  These versatile catalysts promote vital reactions at the very heart of the

  citric acid cycle (the difficult synthesis of citrate from oxaloacetate, for

  instance). Coenzymes also mediate the manufacture of lipids and other

  essential biomolecules. And recently, scientists at Yale discovered

  “riboswitches”—remarkable segments of RNA that change shape when

  they bind to specific molecules in the cell. These chemical sensors then

  regulate the cell’s chemistry by turning genes on and off.

  The inevitable conclusion: RNA is a very ancient molecule that

  seems to “do it all.”

  CAVEATS

  Today, every origin-of-life meeting features sessions dedicated to RNA

  World studies. A thousand articles amplify the idea, and hundreds of

  researchers have pursued variations on the theme. There can be little

  doubt that the emergence of RNA represents a crucial step in life’s ori-

  gin. However, decades of frustrating chemical experiments have dem-

  onstrated that the RNA World could not possibly have emerged fully

  formed from the primordial soup. There must have been some critical

  transition stage that bridged the prebiotic milieu and the RNA World.

  I am persuaded by those who argue that a self-replicating meta-

  bolic system must have emerged first, followed by some form of ge-

  netic molecule that was both structurally simpler and chemically more

  stable than RNA. Only much later did the mechanisms of RNA genet-

  ics and ribozymes come into play. Here are some reasons:

  1. Metabolism, which in its earliest stages uses rather simple

  molecules in the C–O–H (and maybe S) chemical system, seems vastly

  easier to jump-start than genetics. By contrast, the RNA World sce-

  nario relies on exact sequences of chemically complex nucleotides in

  the C–O–H–N–P system. Accordingly, modern cells synthesize nucleic

  acids through metabolism, but RNA synthesis is several steps removed

  THE RNA WORLD

  219

  from the core metabolic cycle, the citric acid cycle. This layering of a

  simple core metabolism surrounded by successively more complex lay-

  ers of synthesis suggests that metabolism came first and other chemi-

  cal pathways were added later.

  2. Many of the presumed protometabolic molecules are synthe-

  sized with relative ease in experiments that mimic prebiotic environ-

  ments, à la Miller–Urey. RNA nucleotides, by contrast, have never been

  synthesized from scratch, in spite of decades of focused effort.

  3. Even if a prebiotic synthetic pathway to nucleotides could be

  found, a plausible mechanism to link those individual nucleotides end-

  to-end into an RNA strand has not been demonstrated. So it’s not ob-

  vious how catalytic RNA sequences would have formed spontaneously

  in any prebiotic environment.

  Sometimes you have to place your bets and put your cards on the

  table. I view the RNA World as a critical, but relatively late, transitional

  stage that occurred when life was well established on Earth—well after

  the emergence of a stable, evolving metabolic world, and before the

  modern DNA-protein world. Biologists seem reasonably confident that

  the last stages of this evolution—the transition from the RNA World

  to a DNA-protein genetic system—can be understood. Top-down stud-

  ies of modern life-forms and the genetic code provide abundant clues

  about that process.

  The greater mystery lies in the seemingly intractable gap between

  primitive metabolism and RNA. Before we can contemplate the RNA

  World, therefore, we have to address the pre-RNA World. By what

  chemical process did the first information-bearing system emerge?

  17

  The Pre-RNA World

  I’ve been waiting all my life for an idea like this.

  Simon Nicholas Platts, 2004

  What preceded the RNA World? We understand a lot about the

  possible earliest stages of life’s emergence—how to make the

  prebiotic soup with all sorts of interesting molecules and how to as-

  semble those molecules into a variety of larger useful structures. At the

  other end of the story, we have a good handle on how strands of RNA

  might function as evolving, self-replicating systems (as we’ll see in the

  next chapter). But there’s that maddening gap between the primordial

  soup and the RNA World. Stanley Miller sums up the problem: “Iden-

  tifying the first gene
tic material will provide the key to understanding

  the origin of life. RNA is an unlikely candidate.”

  To be sure, there have been numerous creative attempts to close

  this gap. Several researchers have approached the problem by propos-

  ing simpler types of precursor genetic polymers that might have arisen

  before RNA. In a tour de force research program, the Swiss chemist

  Albert Eschenmoser explored the stabilities of more than a dozen vari-

  ants of RNA with modified sugar-phosphate backbones. He systemati-

  cally replaced the 5-carbon sugar ribose with various other 4-, 5- and

  6-carbon sugars and discovered seven new kinds of stable nucleic-acid-

  like structures. Most significant was the discovery by Eschenmoser and

  colleagues of a nucleic acid with the 4-carbon sugar threose (the mol-

  ecule was dubbed TNA). Unlike ribose, which must be synthesized

  through a rather cumbersome sequence of chemical steps, threose can

  be assembled directly from a pair of 2-carbon molecules. This differ-

  ence makes TNA a much more likely molecule than RNA to arise spon-

  taneously from the prebiotic soup.

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  GENESIS

  Other scientists took a different chemical tack. In 1991, the Danish

  chemist Peter Nielsen and colleagues synthesized a novel genetic mol-

  ecule—a “peptide nucleic acid” (PNA), which features RNA-like bases

  bound to a backbone of amino acid molecules. The reliance on readily

  available amino acids, rather than problematic sugar phosphates for

  the polymer backbone, appealed to many members of the origins com-

  munity. The discovery of PNA also underscored the chemical richness

  of plausible genetic molecules.

  These immensely creative efforts expand the repertoire of prebi-

  otic possibilities. They also hold the promise of providing new kinds of

  synthetic genetic molecules that can interact with modern cells yet not

  interfere with cellular function—a potential boon to medical research.

  Nevertheless, no one has managed to achieve a plausible prebiotic syn-

  thesis of these alternative nucleotides, much less a viable genetic poly-

  mer. The door is wide open for new ideas.

  THE PAH WORLD

  ***WARNING: The following section presents an intriguing hy-

  pothesis, but one that is highly speculative and as yet untested. Such